CN102803222B - Method and process for preparation and production of deuterated omega-diphenylurea - Google Patents

Abstract

Methods and processes for preparation and production of deuterated omega -diphenylure are disclosed. Especially, a kind of deuterated omega-diphenylurea compounds which can inhibit phosphokinase and the preparation method of N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-1',1',1'-d3-methylcarbamoyl)-4-pyridinyloxy)phenyl)urea are disclosed. The said deuterated diphenylurea compounds can be used for treating or preventing tumors and relative diseases.

Description

A method and process for the synthesis and production of deuterated ω-diphenylurea

technical field

The present invention relates to the field of chemical synthesis, more specifically to a method and process for the synthesis and production of deuterated ω-diphenylurea.

Background technique

Known ω-diphenylurea derivatives are c-RAF kinase active compounds. For example, WO 2000/042012 discloses a class of ω-carboxyaryl substituted diphenylureas and their use in the treatment of cancer and related diseases.

ω-Diphenylurea compounds such as Sorafenib were first discovered as inhibitors of c-RAF kinase, and subsequent studies have found that it can also inhibit MEK and ERK signaling pathways, vascular endothelial growth factor-2 (VEGFR-2), vascular endothelial growth factor-3 (VEGFR-3), and platelet-derived growth factor-β (PDGFR-β) tyrosine kinase activity (CurrPharm Des 2002;8:2255–2257), so It is called a multi-kinase inhibitor and has dual anti-tumor effects.

Sorafenib, trade name Nexavar, is a novel oral multikinase inhibitor jointly developed by Bayer and ONXY, due to its excellent performance in a phase III clinical study for advanced renal cancer , which was fast-approved by the FDA in December 2005 for the treatment of advanced renal cell carcinoma, and was launched in China in November 2006. However, Sorafenib has various side effects, such as high blood pressure, weight loss, rash, etc.

However, there is still a need in the art to develop compounds with inhibitory activity against raf kinase or better pharmacodynamic properties and their preparation processes.

Contents of the invention

The purpose of the present invention is to provide a new type of compound with raf kinase inhibitory activity and better pharmacodynamic performance and its use.

Another object of the present invention is to provide a series of synthetic methods of deuterated ω-diphenylurea and its intermediates, so as to meet the standards in pharmaceutical industry production and improve operability and safety.

In the first aspect of the present invention, there is provided a deuterated ω-diphenylurea compound or a pharmaceutically acceptable salt thereof, said compound is N-(4-chloro-3-(trifluoromethyl )phenyl)-N'-(4-(2-(N-1',1',1'-trideuteromethylcarbamoyl)-4-pyridyloxy)phenyl)urea;

In another preferred example, N in the compound is ¹⁴ N.

In the second aspect of the present invention, there is provided a preparation compound N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-1',1' , 1'-trideuteromethylcarbamoyl)-4-pyridyloxy)phenyl)urea method,

The methods include:

(a) reacting a compound of formula III with a compound of formula V in an inert solvent and in the presence of a base to form said compound;

In the formula, X is Cl, Br, or I;

Alternatively, the method includes:

(b) reacting the compound of formula IX with CD ₃ NH ₂ or CD ₃ NH ₂ ·HCl in an inert solvent to form said compound;

In the formula, R is C1-C8 straight chain or branched chain alkyl, or aryl;

Alternatively, the method includes:

(c) in an inert solvent, 4-chloro-3-trifluoromethylbenzene isocyanate (Ⅷ) reacts with the compound of formula 5 to form the compound;

Alternatively, the method includes:

(d) reacting a compound of formula 5 with a compound of formula ₆ in the presence of CDI and _CH2Cl2 in an inert solvent to form said compound.

In another preference, the compound of formula III is prepared by the following method:

(i) p-Hydroxyaniline (I) and 4-chloro-3-trifluoromethylaniline (II) are condensed to obtain III compound:

In another preference, the compound of formula III is prepared by the following method:

(ii) p-methoxyaniline (X) and 4-chloro-3-trifluoromethylaniline (II) or 4-chloro-3-trifluoromethylbenzene isocyanate (VIII) react to generate XI compound:

Then, compound XI is demethylated under acidic or basic conditions to obtain compound III.

In another preferred example, the compound of formula VII is prepared by the following method:

VI compound and p-hydroxyaniline under the action of alkali, generate VII compound:

In the formula, X is chlorine, bromine or iodine; R is C1-C8 linear or branched alkyl, or aryl.

In another preferred example, the base is selected from potassium tert-butoxide, sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide or combinations thereof.

In another preferred embodiment, the method (a) also includes performing the reaction in the presence of a catalyst, wherein the catalyst is selected from: cuprous iodide and proline; or cuprous iodide and picolinic acid.

In another preferred example, each reaction is carried out at a temperature of 0-200°C.

In a third aspect of the present invention, an intermediate represented by formula B is provided,

In the formula, Y is halogen or

In another preferred embodiment, Y is Cl, and the structural formula is

In a fourth aspect of the present invention, there is provided a method for preparing 4-chloropyridine-2-(N-1',1',1'-trideuteromethyl)amide, comprising the steps of:

(a1) Under basic conditions, in an inert solvent, react methyl 4-chloro-2-pyridinecarboxylate with 1,1,1-trideuteromethylamine or its salt to form 4-chloropyridine- 2-(N-1',1',1'-trideuteromethyl)amide; or

(a2) Reaction of 3-chloro-pyridine-2-formyl chloride with deuterated methylamine in an inert solvent to form 4-chloropyridine-2-(N-1',1',1'-trideuterated Methyl) formamide.

In another preferred example, the inert solvent includes: tetrahydrofuran, ethanol, methanol, water, or a mixed solvent thereof.

In another preferred embodiment, in steps (a1) and (a2), the reaction temperature is -10°C to reflux temperature, preferably -4°C to 60°C, more preferably 5-50°C.

In another preferred embodiment, in steps (a1) and (a2), the reaction time is 0.5-72 hours, preferably 1-64 hours, more preferably 2-48 hours.

In another preferred example, in step (a1), the basic condition is that potassium carbonate, sodium carbonate, cesium carbonate, KOH, NaOH or a combination thereof exists in the reaction system.

In the fifth aspect of the present invention, a method for preparing 4-(4-aminophenoxy)-2-pyridine-(N-1',1',1'-trideuteromethyl)amide is provided, Include steps:

Under basic conditions, 4-chloropyridine-2-(N-1',1',1'-trideuteromethyl)amide was reacted with 4-aminophenol in an inert solvent to form 4-( 4-aminophenoxy)-2-pyridine-(N-1',1',1'-trideuteromethyl)amide

In another preferred embodiment, the basic condition is that KOH, NaOH, potassium carbonate, sodium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, or a combination thereof exists in the reaction system.

In another preferred example, the inert solvent is selected from DMF, DMSO, N,N,-dimethylacetamide, tetrahydrofuran, N-methylpyrrolidone, 1,4-dioxane, or its mixed solvents.

In another preferred embodiment, the above reaction temperature is 0°C to 160°C, preferably 20°C to 120°C, more preferably 30-100°C.

The reaction time is 0.5-48 hours, preferably 1-36 hours, more preferably 3-24 hours.

In the fifth aspect of the present invention, there is provided the use of the intermediate described in the third aspect of the present invention, which is used for the preparation of deuterated diphenyl urea or as a raw material for the preparation of deuterated diphenyl urea.

In another preferred example, the deuterated diphenylurea includes 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureide)-phenoxy)- 2-(N-1',1',1'-trideuteromethyl)pyridinamide (CM4307); and

4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureide)-phenoxy)-2-(N-1',1',1'-trideutero Methyl) pyridinamide p-toluenesulfonate (CM4307·TsOH).

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, we will not repeat them here.

Description of drawings

Fig. 1 is a curve chart of serum drug concentration (ng/ml) after oral administration of 3 mg/kg reference compound CM4306 in male SD rats.

Fig. 2 is a graph showing the serum drug concentration (ng/ml) of male SD rats after oral administration of 3 mg/kg of the compound CM4307 of the present invention.

Figure 3 is a graph showing the inhibitory effects of CM4306 and CM4307 on the nude mouse transplantation model of human hepatocellular carcinoma SMMC-7721. In the figure, "treatment" means that the treatment time is 14 days. This was followed by an observation period after drug withdrawal. The first 5 days of treatment was the model preparation period.

Detailed ways

After research, the inventors unexpectedly found that the deuterated ω-diphenylurea and pharmaceutically acceptable salts thereof of the present invention have significantly better pharmacokinetics and/or compared with undeuterated compounds. or pharmacodynamic properties, so it is more suitable as a compound for inhibiting raf kinase, and thus more suitable for the preparation of drugs for treating cancer and related diseases.

In addition, the inventors have also found that by adopting the new intermediate of formula B,

In the formula, Y is halogen or The high-purity diphenylurea compound can be prepared efficiently and conveniently. The present invention has been accomplished on this basis.

definition

As used herein, "halogen" refers to F, Cl, Br, and I. More preferably, the halogen atoms are selected from F, Cl and Br.

As used herein, "alkyl" includes straight or branched chain alkyl groups. Preferred alkyl groups are C1-C4 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like.

As used herein, "deuterated" refers to the replacement of one or more hydrogens in a compound or group with deuterium. Deuterium can be monosubstituted, disubstituted, polysubstituted or fully substituted. The term "one or more deuterated" and "one or more deuterated" are used interchangeably.

In another preference, the deuterium isotope content of deuterium at the deuterium substitution position is greater than the natural deuterium isotope content (0.015%), more preferably greater than 50%, more preferably greater than 75%, more preferably greater than 95%, more preferably Greater than 97%, more preferably greater than 99%, more preferably greater than 99.5%.

In another preferred embodiment, the compound of formula (I) contains at least 1 deuterium atom, more preferably 3 deuterium atoms, more preferably 5 deuterium atoms.

As used herein, the term "compound CM4306" refers to the compound 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureide)-phenoxy)-N-methylpicolinamide .

As used herein, the term "compound CM4307" refers to the compound 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureide)-phenoxy)-2-(N-1 ',1',1'-trideuteromethyl)pyridinamide.

As used herein, the term "TsOH" means p-toluenesulfonic acid. Thus, CM4307.TsOH represents the p-toluenesulfonate salt of compound CM4307.

deuterated diphenylurea

The preferred deuterated diphenylurea compound of the present invention has the structure of formula I:

In the formula:

X is N or N ⁺ -O ^- ;

^R is halogen (such as F, Cl or Br), one or more deuterated or fully deuterated C1-C4 alkyl;

^R is undeuterated, one or more deuterated or fully deuterated C1-C4 alkyl, or partially or fully halogen substituted C1-C4 alkyl;

R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ are respectively hydrogen, deuterium, or halogen (such as F, Cl, or Br);

^R is hydrogen, deuterium, or one or more deuterated or fully deuterated C1-C4 alkyl;

^R is hydrogen, deuterium, or one or more deuterated or fully deuterated C1-C4 alkyl;

with the proviso that at least one of R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^{9 , R 10 , R 11 , R 12} , R ¹³ or R ¹⁴ is deuterated or deuterated .

In another preferred example, the deuterium isotope content of deuterium at the deuterium substitution position is at least greater than the natural deuterium isotope content (0.015%), preferably greater than 30%, more preferably greater than 50%, more preferably greater than 75%, and more preferably Preferably greater than 95%, more preferably greater than 99%.

In another preferred embodiment, all or substantially (>99wt%) of other elements (such as N, C, O, F, etc.) except H in the compound of formula (I) are the naturally occurring elements with the highest abundance , such as ¹⁴ N, ¹² C, ¹⁶ O and ¹⁹ F.

In another preferred embodiment, the compound of formula (I) contains at least 1 deuterium atom, more preferably 3 deuterium atoms, more preferably 5 deuterium atoms.

In another preference, R ¹ is selected from halogen; more preferably chlorine;

In another preference, R ² is trifluoromethyl;

In another preferred example, ^R6 or ^R7 are independently selected from: hydrogen, deuterium, deuterated methyl, or deuterated ethyl; , trideuteromethyl, one deuterium ethyl, dide deuterium ethyl, three deuterium ethyl, four deuterium ethyl, or penta deuterium ethyl.

In another preferred example, R ⁶ or R ⁷ are independently selected from: hydrogen, methyl or trideuteromethyl.

In another preferred example, R ³ , R ⁴ or R ⁵ are each independently selected from: hydrogen or deuterium.

In another preferred example, R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ are each independently selected from: hydrogen or deuterium.

In another preferred example, R ¹² , R ¹³ or R ¹⁴ are independently selected from hydrogen or deuterium.

In another preferred embodiment, the compound is a preferred compound selected from the following group:

N-(4-Chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-1',1',1'-trideuteromethylcarbamoyl)-4 -pyridyloxy)phenyl)urea;

4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido)phenoxy)-2-(N-1',1',1'-trideuteromethyl Carbamoyl) pyridine-1-oxide;

intermediate

As used herein, the term "intermediate of the present invention" refers to a compound of formula B:

In the formula, Y is halogen or

All or substantially (>99wt%) of the other elements (such as N, C, O, etc.) except H in the compound of the above formula are the most abundant naturally occurring elements, such as ¹⁴ N, ¹² C and ¹⁶ O.

active ingredient

As used herein, the term "compound of the present invention" refers to a compound represented by formula (I). The term also includes the various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (I).

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.

Preparation

The preparation methods of the compound of formula (I) and the intermediate of formula B of the present invention are described in more detail below, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.

Methods for the preparation of the non-deuterated ω-diphenylureas and their physiologically compatible salts used according to the invention are known. The corresponding deuterated ω-diphenylurea can be prepared by using the corresponding deuterated starting compound as raw material, and synthesized by the same route. For example, the compound of formula (I) of the present invention can be prepared according to the preparation method described in WO 2000/042012, the difference being that the raw material used for deuterated substitution in the reaction is used for non-deuterated raw material.

Usually, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C to 80°C, preferably 0°C to 50°C). The reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.

Taking compound CM4307 as an example, a preferred preparation process is as follows:

Synthetic route one

As shown in synthetic route 1, p-hydroxyaniline (compound I) and 3-trifluoromethyl-4-chloro-aniline (compound II) react under the action of N, N'-carbonyldiimidazole, phosgene or triphosgene 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (compound III) is obtained. Methyl picolinate (compound IV) and deuterated methylamine or deuterated methylamine hydrochloride under the action of alkali (such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine, etc.), or direct mixed reaction , to obtain pyridine-2-(N-1',1',1'-trideuteromethyl)carboxamide (compound V). Compound III and compound V are in base (such as potassium tert-butoxide, sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide) and optional catalyst (such as cuprous iodide and proline Amino acid, or cuprous iodide and picolinic acid), the compound CM-4307 is obtained. The above reaction is carried out in an inert solvent, such as dichloromethane, dichloroethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc., at a temperature of 0-200 ° C .

Taking compound CM4307 as an example, another preferred preparation process is as follows:

Synthetic route two

As shown in the synthetic route two, picolinate (compound VI) and p-hydroxyaniline (compound I) in alkali (such as potassium tert-butoxide, sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide , sodium hydroxide) and an optional catalyst (such as cuprous iodide and proline, or cuprous iodide and picolinic acid), the amine (compound VII) is obtained. Then react with compound II under the action of N,N'-carbonyldiimidazole, phosgene or triphosgene, or react with 4-chloro-3-trifluoromethyl-phenylisocyanate (compound VIII) to obtain urea (compound IX). Compound IX reacts with deuterated methylamine or deuterated methylamine hydrochloride under the action of a base (such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine, etc.) or directly to obtain compound CM4307. The above reaction is carried out in an inert solvent, such as dichloromethane, dichloroethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc., at a temperature of 0-200 ° C .

Taking compound CM4307 as an example, another preferred preparation process is as follows:

Synthetic route three

As shown in Synthetic Route 3, p-methoxyaniline (compound X) and compound II are reacted with N, N'-carbonyldiimidazole, phosgene or triphosgene, or with 4-chloro-3-trifluoromethyl- Reaction of phenylisocyanate (compound VIII) affords urea (compound XI). 1-(4-Chloro-3-(trifluoromethyl)phenyl)-3-(4-hydroxyphenyl)urea (compound III) was obtained using various demethylation methods known in the art. Then use the same method as described in Synthetic Scheme 1, or various synthetic methods known in the art to react compound III and compound V to obtain compound CM4307. The above reaction is carried out in an inert solvent, such as dichloromethane, dichloroethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc., at a temperature of 0-200 ° C .

Taking compound CM4307 as an example, a particularly preferred preparation process is as follows:

Synthetic Route 4

Deuterium can be introduced by deuterated methylamine.

Deuterated methylamine or its hydrochloride can be obtained by the following reaction. Nitromethane reacts with deuterium water in alkali (sodium hydride, potassium hydride, deuterated sodium hydroxide, deuterated potassium hydroxide, potassium carbonate, etc.), or under a phase transfer catalyst, to obtain deuterated nitromethane, if necessary , Repeat the above experiment to obtain high-purity deuterated nitromethane. Deuterated nitromethane reduction, such as zinc powder, magnesium powder, iron or nickel, etc., to obtain deuterated methylamine or its hydrochloride.

Furthermore, deuterated methylamine or its hydrochloride can be obtained by the following reaction.

The key intermediate 3 can also be synthesized from deuterated methanol by the following method.

Its specific synthesis method is described in detail in Example 1.

The main advantages of the present invention include:

(1) The compound of the present invention has excellent inhibitory activity against phosphokinase (Kinase) such as raf kinase.

(2) Through the formula B intermediate of the present invention, various deuterated diphenylurea can be prepared conveniently, efficiently and with high purity.

(3) The reaction conditions are milder and the operation process is safer.

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Parts and percentages are by weight unless otherwise indicated.

Example 1: N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-1',1',1'-trideuteromethylaminomethyl Acyl)-4-pyridyloxy)phenyl)urea (compound CM4307)

synthetic route:

Process one

1, Preparation of 4-chloropyridine-2-(N-1',1',1'-trideuteromethyl)formamide (3)

Add thionyl chloride (60mL) into a 250mL single-necked round bottom flask equipped with an exhaust gas treatment device, and maintain the temperature between 40 and 50°C, slowly add anhydrous DMF (2mL) dropwise thereto, and the dropwise addition is complete Afterwards, stirring was continued for 10 minutes, and nicotinic acid (20 g, 162.6 mmol) was added in batches within 20 minutes, and the color of the solution gradually changed from green to light purple. The temperature was raised to 72°C, stirred and refluxed for 16 hours, and a large amount of solid precipitated. Cool to room temperature, dilute with toluene (100 mL), concentrate to near dryness, then dilute again with toluene, concentrate to dryness. Filtration and washing with toluene afforded 3-chloro-pyridine-2-carbonyl chloride as a light yellow solid. The solid was slowly added to a saturated tetrahydrofuran solution of deuterated methylamine under ice-cooling, and the temperature was kept below 5°C, and stirring was continued for 5 hours. Concentrate, add ethyl acetate, precipitate a white solid, filter it off, wash the filtrate with saturated brine, dry over anhydrous sodium sulfate, and concentrate to dryness to obtain light yellow 4-chloropyridine-2-(N-1',1' , 1'-trideuteromethyl) formamide (3) (20.68g), yield 73%.

¹ H NMR (CDCl ₃ , 300MHz): 8.37(d,1H), 8.13(s,1H), 7.96(br,1H), 7.37(d,1H).

2. Preparation of 4-(4-aminophenoxy)-2-pyridine-(N-1',1',1'-trideuteromethyl)formamide (5)

Add p-aminophenol (9.54g, 0.087mol) and potassium tert-butoxide (10.3g, 0.092mol) successively to 100mL dry anhydrous DMF, the solution turns dark brown, after stirring at room temperature for 2 hours, add 4 -Chloropyridine-2-(N-1',1',1'-trideuteromethyl)formamide (3) (13.68g, 0.079mol), anhydrous potassium carbonate (6.5g, 0.0467mol), and After the temperature of the reaction solution rose to 80°C, stirring was continued overnight. TLC detects that the reaction is completed, cooled to room temperature, and the reaction solution is poured into a mixed solution of ethyl acetate (150mL) and saturated brine (150mL), stirred and layered, separated after standing, and the aqueous layer is extracted with ethyl acetate ( 100mL×3), the combined extracts were washed with saturated water (100mL×3), dried over anhydrous sodium sulfate, and concentrated to obtain pale yellow 4-(4-aminophenoxy)-2-pyridine-(N-1 ', 1', 1'-trideuteromethyl)formamide (18.00g), yield 92%.

¹ H NMR(CDCl ₃ ,300MHz):8.32(d,1H),7.99(br,1H),7.66(s,1H),6.91～6.85(m,3H),6.69(m,2H),3.70(br ,s,2H).

3. N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-1',1',1'-trideuteromethylcarbamoyl) Preparation of -4-pyridyloxy)phenyl)urea (CM4307)

Add 5-amino-2-chloro-trifluoromethylbenzene (15.39g, 78.69mol), N,N'-carbonyldiimidazole (CDI) (13.55g, 83.6mmol) to 120mL dichloromethane, stir at room temperature for 16 Hours later, 4-(4-aminophenoxy)-2-pyridine-(N-1',1',1'-trideuteromethyl)formamide (18g, 73mmol) was slowly added dropwise Dichloromethane (180 mL) solution was stirred at room temperature for 18 hours. After the reaction was detected by TLC, part of the dichloromethane solvent was spun off to about 100 mL, left at room temperature for several hours, a large amount of white solid precipitated, filtered with suction, and the solid was washed with a large amount of dichloromethane. After the filtrate was concentrated to remove part of the solvent, part of the solid was precipitated, and the solid was combined twice, and washed again with a large amount of dichloromethane to obtain white powder N-(4-chloro-3-(trifluoromethyl)phenyl)-N '-(4-(2-(N-1',1',1'-trideuteromethylcarbamoyl)-4-pyridyloxy)phenyl)urea CM4307 pure product (20.04g), yield 58 %.

¹ H NMR(CD ₃ OD,300MHz):8.48(d,1H),8.00(d,1H),7.55(m,5H),7.12(d,1H),7.08(s,2H),ESI-HRMS m /z:C21H13D3ClF3N4O3, Calcd.467.11, Found 490.07(M+Na) ⁺ .

In addition, the compound CM4307 can be dissolved in dichloromethane and reacted with peroxybenzoic acid to obtain the corresponding oxidation product: 4-(4-(3-(4-chloro-3-(trifluoromethyl)benzene group) ureido)phenoxy)-2-(N-1',1',1'-trideuteromethylcarbamoyl)pyridine-1-oxide.

Example 2: Preparation of 4-chloropyridine-2-(N-1',1',1'-trideuteromethyl)formamide (3)

a) Dissolve phthalimide (14.7g, 0.1mol), deuterated methanol (3.78g, 0.105mol, 1.05eq), triphenylphosphine (28.8g, 0.11mol, 1.1eq) in anhydrous In THF, DEAD (1.1 eq) THF solution was added dropwise under ice-cooling, and stirred at room temperature for one hour after the dropwise addition was completed. Purify through the column, or after the solvent is spin-dried, add an appropriate amount of DCM to freeze in the refrigerator to precipitate a solid, then filter, spin the filtrate to dryness, and then quickly pass through the column to obtain 14.8 g of pure deuterated methylphthalimide. The yield is 90%.

b) Deuterated methylphthalimide (12.5g, 0.077mol) was dissolved in an appropriate amount of hydrochloric acid (6N, 50ml), and refluxed in a sealed tube for 24-30 hours. After the reaction solution was cooled to room temperature, it was placed in Cool in the refrigerator to below zero, filter the precipitated solid, wash with cold deionized water, collect the filtrate, spin evaporate to remove water and dry to obtain deuterated methylamine hydrochloride. Add anhydrous DCM (100ml) in deuteromethylamine hydrochloride, and add 4-chloronicotinate methyl ester hydrochloride (6.52g, 0.038mol, 0.5eq), sodium carbonate (12.2g, 0.12mol, 1.5 eq), the reaction vial was sealed and placed in a refrigerator for one day of reaction. The reaction was detected by TLC, washed with water after completion, dried, concentrated, and purified by column. The compound 4-chloropyridine-2-(N-1',1',1'-trideuteromethyl)formamide (3) was obtained, 5.67g, with a yield of 86%. Its structural features are consistent with Example 1.

Example 3

Synthesis of compound CM4307

1: Preparation of 4-chloro-3-trifluoromethylphenylisocyanate A4

Dissolve triphosgene (167g, 0.56mol, 0.5eq) in chloroform (500mL), connect the tail gas absorption device, and add N-methylmorpholine (11.4g, 0.11mol, 0.1eq) dropwise in chloroform ( 100 mL) solution, after the dropwise addition was completed, a chloroform (700 mL) solution of 4-chloro-3-trifluoromethylaniline (220 g, 1.13 mol, 1.0 eq) was added dropwise at 10°C. Raise the temperature to 40°C and stir for 15 hours, raise the temperature to 50°C and stir for 5 hours, raise the temperature to 60-65°C and reflux for 5 hours. The solvent was removed under normal pressure, and the fractions at 95-100°C were collected by distillation under reduced pressure (oil temperature 110-120°C, vacuum degree 200Pa) to obtain the title compound as 200 g of a colorless liquid with a purity of 98.7% and a yield of 84%.

2: Preparation of 4-chloropyridine-2-(N-1',1',1'-trideuteromethyl)amide (Intermediate A2)

method 1:

Methyl 4-chloro-2-pyridinecarboxylate (50g, 0.29mol, 1eq) was placed in a three-neck flask filled with 250mL of tetrahydrofuran, stirred and added with 1,1,1-trideuteromethylamine hydrochloride (31g, 0.44mmol, 1.5eq), 400 mesh anhydrous potassium carbonate (80g, 0.58mol, 2eq), stirred at room temperature and reacted for 20 hours, then added water (250mL) and methyl tert-butyl ether (150mL), separated after stirring to obtain The organic phase. The aqueous phase was extracted with methyl tert-butyl ether (100 mL), the organic phases were combined and dried by adding anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure to obtain the title compound as 48 g of light yellow liquid with a purity of 99% and a yield of 96%.

¹ H NMR (DMSO-d6, 400MHz): δ7.64(dd, J=2Hz, 5.2Hz, 1H), 7.97(d, J=1.6Hz, 1H), 8.54(d, J=5.2Hz, 1H) ,8.74(br,1H).

MS(ESI,m/z)calcd.for C ₇ H ₄ D ₃ ClN ₂ O:173,found:174[M+H] ⁺

Method 2:

Dissolve methyl 4-chloro-2-picolinate (130g, 0.76mol, 1eq) in absolute ethanol (1.3L), stir and add 1,1,1-trideuteromethylamine hydrochloride (80g , 1.13mol, 1.5eq), anhydrous potassium carbonate (313g, 2.67mol, 3eq), stirred at room temperature for 50 hours. Filter and wash with ethanol (260mL×2), remove the solvent from the filtrate under reduced pressure, add ethyl acetate (400mL), wash with saturated brine (250mL×2), back-extract the aqueous phase with ethyl acetate (100mL×2), The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure to obtain the title compound as 109 g of light yellow liquid with a purity of 98% and a yield of 83%.

¹ H NMR (DMSO-d6, 400MHz): δ7.64(dd, J=2Hz, 5.2Hz, 1H), 7.97(d, J=1.6Hz, 1H), 8.54(d, J=5.2Hz, 1H) ,8.74(br,1H).

MS(ESI,m/z)calcd.for C ₇ H ₄ D ₃ ClN ₂ O:173,found:174[M+H] ⁺

3: Preparation of 1-(4-chloro-3-trifluoromethyl-phenyl)-3-(4-hydroxy-phenyl)-urea A5

method 1:

4-Amino-phenol (5 g, 45.82 mmol, 1 eq) was dissolved in dichloromethane (40 mL) and 4-chloro-3-trifluoromethylphenylisocyanate (10.7 g, 48.11 mmol, 1.05eq) of dichloromethane (40mL) solution was added dropwise to the above solution, stirred at room temperature for 16 hours, filtered and washed with dichloromethane (10×2) to obtain the title compound as light brown solid 14.2g, purity 97% , yield 94%.

¹ H NMR (DMSO-d6, 400MHz): δ6.70(dd, J=2Hz, 6.8Hz, 1H), 7.22(dd, J=2Hz, 6.4Hz, 1H), 7.58-7.24(m, 1H), 8.10(d,J=2Hz,1H),8.50(br,1H),9.04(br,1H),9.14(br,1H).

MS(ESI,m/z)calcd.for C ₁₄ H ₁₀ ClF ₃ N ₂ O ₂ :330,found:331[M+H] ⁺

Method 2:

4-Chloro-3-trifluoromethylphenyl isocyanate (5.15g, 26mmol, 1.05eq) was dissolved in dichloromethane (30mL), stirred at room temperature for 20 hours, p-methoxyaniline (3.07g, 25mmol, 1eq) of dichloromethane (20mL), stirred at room temperature for 20 hours. Filter and wash with dichloromethane (5mL×2), dissolve the solid in ethyl acetate (50mL), wash with dilute hydrochloric acid (1N, 10mL), wash with saturated brine (20mL), and dry the organic phase over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1-(4-chloro-3-trifluoromethyl-phenyl)-3-(4-methoxy-phenyl)-urea A6 (4.5 g) as a white solid in 52% yield.

¹ H NMR (DMSO-d6, 400MHz): δ3.73(s,3H),6.86-6.90(m,2H),7.35-7.39(m,2H),7.59-7.65(m,2H),8.11(d ,J=2Hz,1H),8.65(br,1H),9.09(br,1H).

MS(ESI,m/z)calcd.for C ₁₅ H ₁₂ ClF ₃ N ₂ O ₂ :344,found:345[M+H] ⁺

1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(4-methoxy-phenyl)-urea A6 (344 mg, 1 mmol, 1 eq) was dissolved in acetic acid (4 mL) and hydrogen was added Bromic acid (40%, 1mL), reflux for 5 hours, cooled to room temperature, and added ice water (10mL), extracted with ethyl acetate (20mL), and washed with saturated sodium bicarbonate solution (10mL), the organic layer was washed with anhydrous After drying over sodium sulfate, the solvent was removed under reduced pressure to obtain the title compound as 140 mg of light yellow solid with a purity of 90% and a yield of 42%.

¹ H NMR (DMSO-d6, 400MHz): δ6.70(dd, J=2Hz, 6.8Hz, 1H), 7.22(dd, J=2Hz, 6.4Hz, 1H), 7.58-7.24(m, 1H), 8.10(d,J=2Hz,1H),8.50(br,1H),9.04(br,1H),9.14(br,1H).

MS(ESI,m/z)calcd.for C ₁₄ H ₁₀ ClF ₃ N ₂ O ₂ :330,found:331[M+H] ⁺

4: 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl]ureide)-phenoxy)-2-(N-1',1',1'-tri Preparation of deuterated methyl) pyridine amide CM4307

1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(4-hydroxy-phenyl)-urea A5 (4 g, 12.10 mmol, 1 eq) was dissolved in N,N- Dimethylformamide (20mL), potassium tert-butoxide (4.6g, 41.13mmol, 3.4eq) was added in batches, the reaction was stirred for 3 hours, and 4-chloropyridine-2-(N-1',1',1 '- Trideuteromethyl)amide (2.3g, 13.31mmol, 1.1eq) and potassium carbonate (0.8g, 6.05mmol, 0.5eq), heated to 80°C and stirred for 1.5 hours. Cool to room temperature, add ethyl acetate (200mL), filter to remove inorganic salts, wash with saturated brine (50mL×3), separate layers, dry the organic layer with anhydrous sodium sulfate, filter to remove the solvent under reduced pressure, add Acetonitrile (15 mL) was refluxed and stirred for 2 hours, cooled to room temperature and filtered to obtain CM4307, which was 3.4 g of a light yellow solid with a purity of 96% and a yield of 60%.

¹ H NMR (DMSO-d6, 400MHz): δ7.15 (dd, J=2.8Hz, 5.6Hz, 1H), 7.17-7.19 (m, 2H), 7.40 (d, J=2.4Hz, 1H), 7.59 -7.69(m,4H),8.13(d,J=2.4Hz,1H),8.51(d,J=6Hz,1H),8.75(br,1H),8.90(br,1H),9.22(br,1H ).

MS(ESI,m/z)calcd.for C ₂₁ H ₁₃ D ₃ ClF ₃ N ₄ O ₃ :467,found:468[M+H] ⁺

Example 4

Synthesis of compound CM4307

1: Preparation of 4-chloropyridine-2-(N-1’,1’,1’-trideuteromethyl)amide (Intermediate A2)

Under the protection of nitrogen, tetrahydrofuran (10.86kg) was added into a 30L reaction kettle, stirring was started, and 1,1,1-trideuteromethylamine hydrochloride (1.50kg, 21.26mol, 1.5eq), 4- Methyl chloro-pyridine-2-carboxylate (2.43kg, 14.16mol, 1eq), anhydrous potassium carbonate (3.92kg, 28.36mol, 2eq). React at 33°C for 15h, add pure water (12.20kg), and extract twice with methyl tert-butyl ether (3.70kg×2), combine the organic layers, add anhydrous sodium sulfate (0.50kg), stir and dry for 1 hour; filter , at a water temperature of 40±2°C and a vacuum degree of ≤-0.09Mpa, the filtrate was precipitated under reduced pressure to obtain the title compound as 2.41kg of light yellow oily liquid with a purity of 99.0% and a yield of 98%.

¹ H NMR (DMSO-d6, 400MHz): δ7.64(dd, J=2Hz, 5.2Hz, 1H), 7.97(d, J=1.6Hz, 1H), 8.54(d, J=5.2Hz, 1H) ,8.74(br,1H).

MS(ESI,m/z)calcd.for C ₇ H ₄ D ₃ ClN ₂ O:173,found:174[M+H] ⁺

2: Preparation of 4-(4-aminophenoxy)-2-pyridine-(N-1',1',1'-trideuteromethyl)amide (Intermediate A3)

method 1:

Under the protection of nitrogen, dimethyl sulfoxide (2.75kg) was added to a 20L reactor, stirring was started, and 4-chloropyridine-2-(N-1',1',1'-trideuteromethyl ) amide (2.41kg, 13.88mol, 1eq), 4-aminophenol (1.62kg, 14.84mol, 1.08eq), and potassium tert-butoxide (1.66kg, 14.79mol, 1.1eq). After the temperature of the kettle was stabilized, the temperature was raised and the inner temperature of the kettle was maintained at 80°C for 4 hours of reaction. After the temperature of the kettle was lowered to 40°C, add isopropanol (7.90kg) to stir and dilute the reaction solution, wash the reaction kettle with isopropanol, and transfer to a 30L reaction kettle; add hydrochloric acid (5.81kg) dropwise under nitrogen protection , after the dropwise addition, stir and centrifugally filter, and add purified water to wash; the centrifuged solid is transferred to a 50L reactor, and purified water (21.00kg) is added to stir to make it all dissolve; under nitrogen protection, slowly add potassium carbonate dropwise The solution was placed in the above-mentioned 50L reaction kettle (2.5kg potassium carbonate dissolved in 7 liters of purified water), and the dropwise addition was completed in about 1.5 hours; the discharge was centrifugally filtered, the product was washed with purified water, and dried in vacuum for 24 hours to obtain the title compound as light brown Crystal 2.72kg, purity 99.9%, yield 78%.

¹ H NMR (DMSO-d6, 400MHz): δ5.19(br,2H),6.66-6.68(m,2H),6.86-6.88(m,2H),7.07(dd,J=2.8Hz,5.6Hz, 1H),7.36(d,J=2.8Hz,1H),8.45(d,J=5.6Hz,1H),8.72(br,1H).

MS(ESI,m/z)calcd.for C ₁₃ H ₁₀ D ₃ N ₃ O ₂ Cl:246,found:247[M+H] ⁺

Method 2:

Dissolve 4-chloropyridine-2-(N-1',1',1'-trideuteromethyl)amide (4.3g, 24.77mmol, 1eq) in tetrahydrofuran (20mL) at room temperature and stir at room temperature And 4-aminophenol (2.7g, 24.77mmol, 1eq), tetrabutylammonium hydrogensulfate (1.68g, 4.95mmol, 0.2eq), sodium hydroxide solid (1.35g, 33.69mmol, 1.36eq) were added. A 45% aqueous sodium hydroxide solution (sodium hydroxide (1.32 g) dissolved in water (1.6 mL)) was slowly added dropwise, heated to 67° C. and stirred for 20 hours. After cooling to 20°C, 37% concentrated hydrochloric acid (10 mL) was added at such a rate that the temperature of the reaction mixture did not exceed 25°C. Stir for 1 hour, filter and wash with tetrahydrofuran (20 mL), dissolve the obtained solid in water (60 mL), lower the temperature of the reaction solution to 10-20 ° C, slowly add dropwise 22.5% sodium hydroxide solution (2.6 mL)), Adjust pH=3-3.5, continue to dropwise add 22.5% sodium hydroxide solution (3.4mL), adjust pH=7-8, a light yellow solid precipitates out, keep the system temperature not exceeding 20 degrees during the dropping process. Filtered and washed with water (12mL×2), dried in vacuo to obtain light yellow 4-(4-amino-phenoxy)-N-deuteromethylpyridine-2-carboxamide 5.01g, purity 99%, yield was 82%.

¹ H NMR (DMSO-d6, 400MHz): δ5.19(br,2H),6.66-6.68(m,2H),6.86-6.88(m,2H),7.07(dd,J=2.8Hz,5.6Hz, 1H),7.36(d,J=2.8Hz,1H),8.45(d,J=5.6Hz,1H),8.72(br,1H).

MS(ESI,m/z)calcd.for C ₁₃ H ₁₀ D ₃ N ₃ O ₂ Cl:246,found:247[M+H] ⁺

3: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureide)-phenoxy)-2-(N-1',1',1'-tri Preparation of deuterated methyl) pyridine amide (CM4307)

Under the protection of nitrogen, add dichloromethane (17.30kg) and dimethyl sulfoxide (2.92kg) to the 50L dry reactor, stir at room temperature and add 4-(4-aminophenoxy)-2-pyridine-(N -1',1',1'-trideuteromethyl)amide (2.65 kg, 10.76 mol). 4-Chloro-3-trifluoromethylphenyl isocyanate (2.50kg, 11.26mol, 1.05eq) was dissolved in dichloromethane (7.00kg), and added dropwise to the reaction kettle, reacted at room temperature for 10min, washed with ice brine down to 3±2°C. Add 10.60kg of purified water dropwise to the reaction kettle, and control the temperature at 3±2°C, continue to stir for 30 minutes after the drop is completed, discharge the material and centrifugally filter, wash the product with dichloromethane (7.00kg), and vacuum the obtained product After drying for 24 hours, 4.8 kg of off-white powdery solid was obtained, with a purity of 99.8% and a yield of 95.4%.

¹ H NMR (DMSO-d6, 400MHz): δ7.15 (dd, J=2.8Hz, 5.6Hz, 1H), 7.17-7.19 (m, 2H), 7.40 (d, J=2.4Hz, 1H), 7.59 -7.69(m,4H),8.13(d,J=2.4Hz,1H),8.51(d,J=6Hz,1H),8.75(br,1H),8.90(br,1H),9.22(br,1H ).

MS(ESI,m/z)calcd.for C ₂₁ H ₁₃ D ₃ ClF ₃ N ₄ O ₃ :467,found:468[M+H] ⁺

Example 5

4: 4-(4-(3-(4-Chloro-3-(trifluoromethyl)phenyl]ureide)-phenoxy)-2-(N-1',1',1'-tri Preparation of deuterated methyl)pyridinamide p-toluenesulfonate (CM4307·TsOH)

Add absolute ethanol (45.00kg) to a 100L reactor, start stirring, and add 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureide)-phenoxy base)-2-(N-1',1',1'-trideuteromethyl)pyridinamide (4.50kg, 9.62mol, 1eq) and p-toluenesulfonic acid monohydrate (0.66kg, 3.47mol, 0.36 eq), the temperature was raised to 78° C. and refluxed for 40 minutes until all the solids were dissolved.

Dissolve p-toluenesulfonic acid monohydrate (1.61kg, 8.46mol) in absolute ethanol (4.50kg) and heat up to 70°C to dissolve. Then add the solution into the above-mentioned 100L reaction kettle, lower the temperature to 0-2°C, and keep the temperature for 30 minutes. The material was discharged and centrifugally filtered, the product was washed with absolute ethanol (13.50 kg), and dried in vacuum for 24 hours to obtain the title compound as a white to off-white solid of 5.75 kg with a purity of 99.3% and a yield of 93.4%.

¹ H NMR (DMSO-d6, 400MHz): δ2.30(s,3H),7.15(d,J=8.8Hz,2H),7.20(d,J=8.8Hz,2H),7.23(dd,J= 2.8Hz,6Hz,1H),7.52(d,J=8Hz,2H),7.55(d,J=2.8Hz,1H),7.63(d,J=8.8Hz,3H),7.68(dd,J=2.4 Hz,9.2Hz,1H),8.03(br,1H),8.14(d,J=2.4Hz,1H),8.56(d,J=6Hz,1H),8.91(br,1H),9.17(br,1H ),9.36(br,1H).

¹³ C NMR (DMSO-d6, 400MHz): δ21.1, 26.1, 111.7, 115.2, 117.0, 120.7(2C), 121.6(2C), 121.9, 122.8, 123.2, 124.6, 125.6(2C), 127.2, 129.0( 2C), 132.3, 138.8, 139.5, 139.9, 144.1, 146.6, 147.2, 152.8, 159.9, 170.7ppm.

Liquid conditions: Agilent 1100Series; Chromatographic column: Synergi 4μPOLAR-RP 80A, 250×4.6mm, 4μm; Column temperature: 25℃; Detection wavelength: UV 210nm; Mobile phase: A: Ammonium dihydrogen phosphate 10mmol/L, B: Methanol; Injection volume: 10 μL; Flow rate: 0.8 mL/min; Analysis time: 70 min; Gradient program: 0 to 15 min 50% mobile phase B, 15 to 32 min to 75% mobile phase B, then 32 to 55 min 75% mobile phase B was eluted for 23 minutes. Retention time: 4.95min (p-toluenesulfonic acid); 47.11min (CM4307).

Example 6

Synthesis of compound CM4307

1: Preparation of tert-butyl 4-chloropyridine-2-carboxylate A7

Suspend 4-chloropyridine-2-carboxylic acid (10.5g, 66.64mmol) in thionyl chloride (40mL), heat up to 80°C and reflux, add N,N-dimethylformamide (0.2mL) dropwise, and reflux 2 hours. Dimethylsulfoxide was removed under reduced pressure to give a pale yellow acid chloride, and dichloromethane (60 mL) was added. At -40°C, the dichloromethane solution prepared above was added dropwise to a mixed solution of tert-butanol (25 mL), pyridine (20 mL) and dichloromethane (80 mL). The reaction solution was warmed up to 50°C and stirred for 16 hours. The solvent was removed under reduced pressure, ethyl acetate (150 mL) was added, washed with saturated brine (50 mL×2), and then washed with sodium hydroxide solution (1N) (50 mL×2), the layers were separated, and the organic phase was washed with anhydrous sodium sulfate Dry, remove the solvent under reduced pressure, and dry in vacuo to obtain the title compound as 11.1 g of a light yellow solid with a purity of 95% and a yield of 78%.

¹ H NMR (DMSO-d6, 400MHz): δ1.56(s, 9H), 7.80(dd, J=2.4Hz, 5.2Hz, 1H), 8.02(d, J=2Hz, 1H), 8.69(d, J=5.2Hz,1H).

MS(ESI,m/z)calcd.for C ₁₀ H ₁₂ ClNO ₂ :213,found:158[M- ^But +H] ⁺

2: Preparation of tert-butyl 4-(4-amino-phenoxy)-pyridine-2-carboxylate A8

At room temperature, p-aminophenol (0.51g, 4.70mmol, 1eq) was dissolved in N,N-dimethylformamide (10mL), and potassium tert-butoxide (0.53g, 4.70mmol, 1eq) was added in portions and stirred for 0.5 After 1 hour, tert-butyl 4-chloropyridine-2-carboxylate (1 g, 4.70 mmol, 1 eq) and potassium carbonate (45 mg, 0.33 mmol, 0.07 eq) were added, heated to 80° C. and stirred for 2 hours. Cooled to room temperature, added ethyl acetate (50mL), filtered to remove insoluble matter, added saturated brine to wash (20mL×2), organic phase was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and column chromatography (dichloromethane : ethyl acetate=30:1) to obtain the title compound 805mg, purity 96%, yield 60%.

¹ H NMR (DMSO-d6, 400MHz): δ1.52(s,9H),5.21(br,2H),6.64(d,J=8.8Hz,2H),6.87(d,J=8Hz,2H), 7.35(dd,J=2.4Hz,5.6Hz,1H),8.50(d,J=6Hz,1H).

MS(ESI,m/z)calcd.for C ₁₀ H ₁₂ ClNO ₂ :286,found:231[M- ^But +H] ⁺

3: Preparation of tert-butyl 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylate A9

4-Chloro-3-trifluoromethylphenylisocyanate (656 mg, 2.96 mmol, 1.05 eq) was dissolved in dichloromethane (5 mL) at room temperature, and 4-(4-amino-phenoxy)- A solution of tert-butyl pyridine-2-carboxylate (805 mg, 2.81 mmol, 1 eq) in dichloromethane (5 mL) was slowly added dropwise to the above solution, and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, and the obtained solid was separated by column chromatography (dichloromethane:methanol=30:1) to obtain the compound as 1.4 g of white solid with a purity of 95% and a yield of 85%.

¹ H NMR (DMSO-d6, 400MHz): δ1.53(s, 9H), 7.13(dd, J=2.4Hz, 5.2Hz, 1H), 7.18(d, J=8.8Hz, 2H), 7.41(d ,J=2.4Hz,1H),7.59-7.66(m,4H),8.13(d,J=1.6Hz,1H),8.55(d,J=5.6Hz,1H),9.06(br,1H),9.27 (br,1H).

MS(ESI,m/z)calcd.for C ₂₄ H ₂₁ ClF ₃ N ₃ O ₄ :507,found:508[M+H] ⁺

4: Preparation of 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid A10

At room temperature, tert-butyl 4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-urea]-phenoxy}-pyridine-2-carboxylate (1.4 g, 2.76 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (20 mL) and triethylsilane (0.5 mL) were added, and the temperature was raised to 50° C. and stirred for 16 hours. The solvent was removed under reduced pressure, water (50 mL) and ethyl acetate (70 mL) were added, the layers were separated, the organic phase was removed, and the aqueous layer was filtered and washed with water (30 mL×2) to give the title compound as a light green solid, vacuum-dried 1.1 g, purity 97%, yield 90%.

¹ H NMR (DMSO-d6, 400MHz): δ7.21-7.25(m,2H),7.33(dd,J=2.8Hz,6Hz,1H),7.57(d,J=2.8Hz,1H),7.60- 7.67(m,4H),8.12(d,J=2.4Hz,2H),8.64(d,J=6Hz,1H),9.84(br,1H),10.17(br,1H),.

MS(ESI,m/z)calcd.for C ₂₀ H ₁₂ ClF ₄ N ₃ O ₄ :451,found:450[MH] ^-

5: 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl]ureide)-phenoxy)-2-(N-1',1',1'-tri Preparation of deuterated methyl) pyridine amide CM4307

method 1:

4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-urea]-phenoxy}-pyridine-2-carboxylic acid (0.5 g, 1.11 mmol, 1 eq. ) was dissolved in N,N-dimethylformamide (5mL), and 1,1,1-trideuteromethylamine hydrochloride (0.15g, 2.22mmol, 2eq), 2-(7-azobenzo Triazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 0.84g, 2.22mmol, 2eq) and N,N-diisopropylethylamine (DIEA, 0.86g , 6.66mmol, 3eq), and stirred at room temperature for 16 hours. Add water (20 mL) dropwise to the above reaction solution, stir for 0.5 hours, filter to obtain an off-white solid, add ethyl acetate (50 mL), wash with saturated brine (10 mL×3), separate layers, and dry the organic phase with anhydrous sodium sulfate , filtered, and the solvent was removed under reduced pressure to obtain 0.42 g of off-white solid CM4307 with a purity of 97% and a yield of 81%.

¹ H NMR (DMSO-d6, 400MHz): δ7.15 (dd, J=2.8Hz, 5.6Hz, 1H), 7.17-7.19 (m, 2H), 7.40 (d, J=2.4Hz, 1H), 7.59 -7.69(m,4H),8.13(d,J=2.4Hz,1H),8.51(d,J=6Hz,1H),8.75(br,1H),8.90(br,1H),9.22(br,1H ).

MS(ESI,m/z)calcd.for C ₂₁ H ₁₃ D ₃ ClF ₃ N ₄ O ₃ :467,found:468[M+H] ⁺

Method 2:

4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-urea]-phenoxy}-pyridine-2-carboxylic acid (0.5 g, 1.11 mmol) was suspended in methanol (10 mL ), add concentrated sulfuric acid (2mL) at room temperature and reflux for 3 hours, remove the solvent under reduced pressure, and separate by column chromatography (dichloromethane:methanol=10:1) to obtain a white solid 4-{4-[3-(4- Chloro-3-trifluoromethyl-phenyl)-ureido]-phenoxy}-pyridine-2-carboxylic acid methyl ester A11 (0.46g), purity 95%, yield 90%.

¹ H NMR (DMSO-d6, 400MHz): δ3.85(s,3H),7.18-7.21(m,3H),7.43(d,(dd,J=2.4Hz,1H),7.59-7.66(m, 4H),8.13(d,J=2.4Hz,1H),8.59(d,J=6Hz,1H),9.06(br,1H),9.27(br,1H),.

MS(ESI,m/z)calcd.for C ₂₁ H ₁₅ ClF ₃ N ₃ O ₄ :465,found:466[M+H] ⁺

4-{4-[3-(4-Chloro-3-trifluoromethyl-phenyl)-urea]-phenoxy}-pyridine-2-carboxylic acid methyl ester (300 mg, 0.65 mmol, 1 eq) was placed in In a three-necked flask containing 10 mL of tetrahydrofuran, stir and add 1,1,1-trideuteromethylamine hydrochloride (91 mg, 1.3 mmol, 2 eq), 400 mesh anhydrous potassium carbonate (179 mg, 1.3 mmol, 2 eq), After stirring at room temperature for 20 hours, water (5 mL) and methyl tert-butyl ether (15 mL) were added, stirred and separated to obtain an organic phase. The aqueous phase was extracted with methyl tert-butyl ether (10 mL), the organic phases were combined, dried by adding anhydrous sodium sulfate and filtered, and the solvent was removed under reduced pressure to obtain 261 mg of CM4307 off-white solid with a purity of 96% and a yield of 86%.

¹ H NMR (DMSO-d6, 400MHz): δ7.15 (dd, J=2.8Hz, 5.6Hz, 1H), 7.17-7.19 (m, 2H), 7.40 (d, J=2.4Hz, 1H), 7.59 -7.69(m,4H),8.13(d,J=2.4Hz,1H),8.51(d,J=6Hz,1H),8.75(br,1H),8.90(br,1H),9.22(br,1H ).

MS(ESI,m/z)calcd.for C ₂₁ H ₁₃ D ₃ ClF ₃ N ₄ O ₃ :467,found:468[M+H] ⁺

Embodiment 7:

Pharmacokinetic Evaluation of Deuterated Diphenylurea Compounds in Rats

8 male Sprague-Dawley rats, 7-8 weeks old, weighing about 210g, were divided into 2 groups, 4 rats in each group (rat number: 13-16 in the control group; 9-12 in the experimental group), orally administered once Administer 3 mg/kg dose of (a) to the composition: undeuterated N-(4-chloro-3-(trifluoromethyl)phenyl)-N'-(4-(2-(N-methyl Carbamoyl)-4-pyridyloxy)phenyl)urea (comparative compound CM4306) or (b) N-(4-chloro-3-(trifluoromethyl)phenyl)-N' prepared in Example 1 -(4-(2-(N-1',1',1'-trideuteromethylcarbamoyl)-4-pyridyloxy)phenyl)urea (compound CM4307 of the present invention), compare its pharmacokinetics academic difference.

Rats were fed with standard diet and given water and lidianine. The night before the experiment, the administration of chlordiazepoxide was stopped, and the administration of chlordiazepoxide was resumed 2 hours after the administration. Fasting started 16 hours before the test. Drugs were dissolved in 30% PEG400. Orbital blood was collected at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours and 24 hours after administration.

The rats were temporarily anesthetized after inhalation of ether, and 300uL blood samples were collected from the orbits in test tubes. There is 30ul 1% heparin salt solution in the test tube. The test tubes were dried overnight at 60°C before use. After blood samples were collected at a later time point, the rats were anesthetized with ether and sacrificed.

Immediately after blood sample collection, gently invert the tube at least 5 times to ensure thorough mixing and place on ice. Blood samples were centrifuged at 5000 rpm at 4°C for 5 minutes to separate serum from red blood cells. Aspirate 100 uL of serum with a pipette into a clean plastic centrifuge tube, indicating the name and time point of the compound. Serum was stored at -80°C until LC-MS analysis.

The result is shown in Figure 1-2. The results showed that the half-life T _1/2 of CM4307 was longer than that of CM4306 [11.3±2.1 hours and 8.6±1.4 hours respectively], and the area under the curve AUC _0-∞ was significantly increased compared with CM4306 [11255±2472ng h/mL and 7328±336ng h/mL], the apparent clearance rate of CM4307 was lower than that of CM4306 [275±52mL/h/kg and 410±18.7mL/h/kg respectively].

It can be seen from the above results that the compound of the present invention has better pharmacokinetics in animals, and thus has better pharmacodynamics and treatment effects.

In addition, through deuteration, the metabolic process of the compounds of the present invention in organisms is changed. Especially the hydroxylation on phenyl groups is made difficult, which leads to a reduction of the first-pass effect. In this case, the dosage can be varied and a depot formulation can be made, which can also improve applicability in the form of a depot formulation.

In addition, the pharmacokinetic effect is also changed by deuteration, because the deuterated compound completely forms another hydrate film, so that the distribution in the organism is significantly different from that of the non-deuterated compound.

Example 8: Pharmacodynamic evaluation of CM4307 on growth inhibition of human hepatocellular carcinoma SMMC-7721 xenografted tumor in nude mice

Balb/c nu/nu nude mice, 6 weeks old, female, 70, were purchased from Shanghai Experimental Animal Resource Center (Shanghai Sipro-Bicai Laboratory Animal Co., Ltd.).

SMMC-7721 cells were purchased from Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences (Shanghai, China).

Establishment of tumor transplantation model in nude mice: Harvest SMMC-7721 cells in the logarithmic growth phase, count and suspend the cells in 1×PBS, and adjust the concentration of the cell suspension to 1.5×10 ⁷ /ml. Tumor cells were inoculated subcutaneously in the right armpit of nude mice with a 1ml syringe, 3×10 ⁶ /0.2ml/mouse. A total of 70 nude mice were inoculated.

When the tumor volume reached 30-130 mm ³ , the animals were randomly divided into groups, and a total of 58 animals were obtained, so that the difference of the tumors in each group was less than 10% of the mean value, and the administration was started.

The test dose grouping settings are shown in the table below:

group animal compound Method of administration Dose (mg/kg) plan 1 10 Blank control (solvent) po 0.1ml/10gBW qdx2 weeks 2 8 CM4306 po 10mg/kg qdx2 weeks

3 8 CM4306 po 30mg/kg qdx2 weeks 4 8 CM4306 po 100mg/kg qdx2 weeks 5 8 CM4307 po 10mg/kg qdx2 weeks 6 8 CM4307 po 30mg/kg qdx2 weeks 7 8 CM4307 po 100mg/kg qdx2 weeks

Animal body weight and tumor size were measured twice a week during the experiment. Clinical symptoms were observed and recorded daily. At the end of the administration, photographs were taken to record the tumor size. One mouse in each group was sacrificed to take tumor tissue, which was fixed in 4% paraformaldehyde. After the administration, the observation was continued. When the average size of the tumor was greater than 2000mm ³ , or the animal appeared to be dying, the animal was sacrificed, grossly dissected, and the tumor tissue was fixed in 4% paraformaldehyde.

The calculation formula of tumor volume (Tumor volume, TV) is: TV=a×b ² /2. Where a and b represent the measured length and width of the tumor, respectively. The formula for calculating relative tumor volume (RTV) is: RTV=Vt/V ₀ . Where V ₀ is the tumor volume at the time of group administration, and Vt is the tumor weight at the time of measurement. The evaluation index of anti-tumor activity is the relative tumor proliferation rate T/C (%), and the calculation formula is: T/C (%)=(T _RTV /C _RTV )×100%. T _RTV is the RTV of the treatment group, and C _RTV is the RTV of the negative control group.

Efficacy evaluation criteria: relative tumor proliferation rate T/C (%) ≤ 40% and statistical analysis p < 0.05 is effective.

The result is shown in Figure 3. CM4306 and CM4307 were given a single dose of 10, 30, 100 mg/kg by intragastric administration daily for 2 consecutive weeks, and both compounds exhibited dose-dependent inhibition of tumor growth. At the end of dosing, the T/C% of CM4306 were 56.9%, 40.6% and 32.2%, respectively. The T/C(%) of CM4307 are 53.6%, 40.8% and 19.6%, respectively. Among them, the T/C% of the 100mg/kg dose group were all <40%, and the tumor volume was significantly different from that of the control group (p<0.01), showing a significant effect of inhibiting tumor growth.

The high-dose 100 mg/kg group of CM4307 had a stronger tumor inhibitory effect than the high-dose CM4306 group (best T/C% were 19.6% and 32.2%, respectively, d15), and there was a significant difference in tumor volume between groups (p<0.01). Compared with CM4306, the absolute value of the tumor inhibition rate of CM4307 increased by more than 10%, and the relative range increased by about 60% (32.2%/19.6%-1=64%), showing a more significant effect of inhibiting tumor growth.

In addition, no other drug-related toxic reactions were observed during the test.

Embodiment 9 pharmaceutical composition

Compound CM4307 (Example 1) 20g

Starch 140g

Microcrystalline Cellulose 60g

According to a conventional method, after the above-mentioned substances are mixed uniformly, they are packed into ordinary gelatin capsules to obtain 1000 capsules.

All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (7)

1. prepare the method for compound N-(the chloro-3-of 4-(trifluoromethyl) phenyl)-N '-(4-(2-(N-1 ', 1 ', 1 '-three deuterium methylcarbamoyl)-4-pyridyl oxygen) phenyl) urea for one kind,

It is characterized in that, described method comprises:

C (), in inert solvent, 4-chloro-3-trifluoromethyl phenylisocyanate (VIII) and formula 5 compound react, the compound described in formation, and wherein said inert solvent is the mixed solvent of methyl-sulphoxide and methylene dichloride;

Wherein, deuterium is be greater than 99% in the deuterium isotopic content of deuterium the position of substitution.

2. the method for claim 1, is characterized in that, described formula 5 compound is prepared by following the method:

I 4-chloropyridine-2-(the deuterated methyl of N-1', 1', 1'-tri-) acid amides (3) and para hydroxybenzene amine (4) react by (), obtain compound 5;

3. method as claimed in claim 2, it is characterized in that, described formula 5 compound method for making is as follows:

Under nitrogen protection, the methyl-sulphoxide of 2.75kg is joined in the reactor of 20L, open and stir, drop into 2.41kg 4-chloropyridine-2-(N-1 ', 1 ', 1 '-three deuterated methyl) acid amides, 1.62kg PAP, then drop into the potassium tert.-butoxide of 1.66kg; After still temperature is stable, heats up and keep temperature 80 DEG C in still to react 4 hours; By after still temperature drop to 40 DEG C, add the Virahol agitation and dilution reaction solution of 7.90kg, then use washed with isopropyl alcohol reactor, and be transferred to the reactor of 30L; Drip the hydrochloric acid of 5.81kg under nitrogen protection, after dropwising, stir and centrifuging, and add purified water washing; Centrifugal solid proceeds to the reactor of 50L, and the purified water adding 21.00kg stirs and makes it whole dissolving; Under nitrogen protection, slowly drip solution of potassium carbonate in above-mentioned 50L reactor, described solution of potassium carbonate is 2.5kg salt of wormwood is dissolved in the solution that 7 liters of purified water obtain, and within 1.5 hours, dropwises; Blowing centrifuging, uses purified water cleaning product, and vacuum-drying 24 hours, obtain formula 5 compound.

4. the intermediate shown in formula B,

In formula, Y is

5. prepare the method for 4-chloropyridine-2-(N-1 ', 1 ', 1 '-three deuterated methyl) acid amides for one kind, it is characterized in that, comprise step:

(a1) in the basic conditions, in inert solvent, 4-Chloro-2-Pyridyle methyl-formiate and the deuterated methylamine hydrochloride of 1,1,1-tri-are reacted, thus formation 4-chloropyridine-2-(N-1 ', 1 ', 1 '-three deuterated methyl) acid amides.

6. the purposes of intermediate as claimed in claim 4; it is characterized in that; for the preparation of deuterated diphenyl urea; described deuterated diphenyl urea be N-(the chloro-3-of 4-(trifluoromethyl) phenyl)-N '-(4-(2-(N-1 '; 1 '; 1 '-three deuterium methylcarbamoyl)-4-pyridyl oxygen) phenyl) urea

7. the purposes of intermediate as claimed in claim 4, it is characterized in that, for the preparation of deuterated diphenyl urea, described deuterated diphenyl urea is 4-(4-(3-(the chloro-3-of 4-(trifluoromethyl) phenyl] uride)-phenoxy group)-2-(N-1', the deuterated methyl of 1', 1'-tri-) picolinamide tosilate.